Updated January 22, 2025
By Anthony M. Calabro, MA

Myelofibrosis (MF) is a rare, chronic myeloproliferative neoplasm (MPN) characterized by bone marrow fibrosis, extramedullary hematopoiesis, and debilitating constitutional symptoms.¹ Patients with MF often experience severe anemia, splenomegaly, and systemic symptoms such as fever, night sweats, and weight loss, which can significantly impact quality of life. The median survival of patients varies widely, depending on risk stratification, with high-risk patients having a survival rate of fewer than 3 years.

The pathogenesis of MF involves dysregulation of hematopoiesis and the bone marrow microenvironment. Driver mutations in the Janus kinase 2 (JAK2), calreticulin (CALR), and myeloproliferative leukemia virus oncogene (MPL) are central to disease development. JAK2 V617F is the most common mutation, present in approximately 60% of patients, while CALR and MPL mutations account for 20% and 5% to 10%, respectively.¹ Other mutations, such as ASXL1, SRSF2, and EZH2, contribute to disease progression and generally a worse prognosis.²

Epigenetic regulators, such as TET2 and DNMT3A, are frequently mutated in MF and are associated with clonal hematopoiesis.³ Dysregulated signaling pathways, including the JAK-STAT, PI3K-AKT, and MAPK pathways, further contribute to the pro-inflammatory and fibrotic environment of the bone marrow. These insights have provided a foundation for targeted therapeutic development aimed at mitigating disease progression.

Inflammatory cytokines play a role in disease manifestations, promoting fibrosis, anemia, and systemic symptoms. Elevated levels of transforming growth factor-β (TGF-β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) are hallmark features, highlighting the interplay between clonal hematopoiesis and the inflammatory milieu.³ In addition, the bone marrow microenvironment—including stromal cells, mesenchymal stem cells, and extracellular matrix components—contributes to the fibrotic process, further impairing hematopoiesis.

MF is typically diagnosed based on clinical presentation, laboratory findings, and bone marrow biopsy. Splenomegaly, often palpable on physical examination, is a hallmark sign, accompanied by symptoms such as fatigue, weight loss, and night sweats. Laboratory tests would generally reveal anemia, leukocytosis, or thrombocytosis, along with circulating immature blood cells (leukoerythroblastosis).

The World Health Organization 2016 criteria for MF include the presence of bone marrow fibrosis grade ≥ 2, JAK2, CALR, or MPL mutations, and at least one clinical feature such as splenomegaly or constitutional symptoms.⁴ Recent updates emphasize the role of next-generation sequencing (NGS) for detecting high-risk mutations, which can refine prognostic models like the Dynamic International Prognostic Scoring System.⁵ Incorporating molecular profiling into routine diagnostic workflows allows clinicians to identify subgroups of patients with distinct prognoses and therapeutic needs.

Advanced imaging techniques, such as magnetic resonance imaging and positron emission tomography, have also been explored for assessing bone marrow fibrosis and splenic involvement.⁶ These modalities, while not routinely used, offer non-invasive tools for monitoring disease progression and therapeutic responses. Additionally, new biomarkers, including circulating CALR levels and cytokine profiles, are under investigation for their potential to enhance diagnostic accuracy and predict outcomes.

Management of MF is tailored to risk stratification and symptom burden. Low-risk patients are typically managed with observation, while higher-risk patients require more aggressive interventions. Transfusions and corticosteroids remain standard management options. Androgens, erythropoiesis-stimulating agents, and immunomodulatory drugs, such as thalidomide and lenalidomide, have been used to address anemia, though their efficacy is often limited.

Ruxolitinib, a JAK1/2 inhibitor, remains the cornerstone of MF treatment. Studies such as the COMFORT-I and COMFORT-II trials demonstrated significant reductions in spleen size and improvements in quality of life.⁶ Fedratinib, another JAK2-selective inhibitor, has shown efficacy in ruxolitinib-refractory patients, as evidenced by the JAKARTA and JAKARTA-2 trials.⁷

The advent of JAK inhibitors has transformed the therapeutic landscape of MF by targeting the underlying pathophysiology and alleviating disease-associated symptoms. However, limitations such as myelosuppression and suboptimal responses in certain subgroups highlight the need for alternative approaches. Emerging data suggest that earlier initiation of JAK inhibitors in intermediate-risk patients may delay disease progression and enhance survival outcomes.⁸

Pacritinib, a JAK2/FLT3 inhibitor, has gained attention for its efficacy in patients with severe thrombocytopenia, a subgroup with limited treatment options. The PERSIST-2 trial reported a 22% spleen volume reduction and improved symptom scores.⁸ Momelotinib, targeting JAK1/2 and ACVR1, has shown promise in alleviating anemia and reducing transfusion dependency in phase 3 studies.⁹ Additional agents, such as navitoclax, a BCL-2/BCL-XL inhibitor, are under investigation for their potential to target MF stem cells and improve survival rates.¹⁰

Advances in understanding the molecular pathways in MF have spurred development of therapies targeting specific mutations and signaling cascades. For instance, BET inhibitors (pelabresib) and antifibrotic agents (PRM-151) are under investigation in combination with JAK inhibitors.¹⁰ Early-phase trials suggest these combinations may enhance spleen responses and improve overall survival.

Combination strategies aim to address the multifaceted nature of MF by targeting both clonal hematopoiesis and the inflammatory microenvironment. These approaches have shown preliminary success in preclinical models and early-phase clinical trials, offering a potential paradigm shift in MF treatment. Additionally, agents targeting the TGF-β and CXCL12 pathways are in development, reflecting the expanding repertoire of therapeutic targets.

Allogeneic hematopoietic stem cell transplantation remains the only potential curative option for MF. The procedure is typically reserved for high-risk patients due to its associated morbidity and mortality. Advances in reduced-intensity conditioning regimens and donor selection have improved outcomes, with 5-year survival rates of 40% to 60% reported in recent cohorts.¹¹ Optimal timing and patient selection remain critical to maximizing benefits.

Recent guidelines emphasize the importance of integrating molecular risk factors, such as high-molecular-risk mutations, into transplant decision-making algorithms. Post-transplant maintenance strategies, including the use of JAK inhibitors and immunomodulatory agents, are being explored to prevent relapse and enhance long-term outcomes.

The treatment landscape of MF continues to evolve, driven by advances in molecular genetics and drug development. JAK inhibitors remain the backbone of therapy, but novel agents targeting specific pathways offer additional options, particularly for patients with refractory or high-risk disease. Incorporating molecular profiling into routine practice and leveraging combination strategies will likely shape the future of MF management. Ongoing research is expected to refine risk stratification and expand therapeutic possibilities, offering hope for improved outcomes in this challenging disease.

Multidisciplinary collaboration among hematologists, transplant specialists, and researchers is essential to address the unmet needs of MF patients. Continued investment in basic and translational research will be pivotal in uncovering new therapeutic targets and optimizing treatment algorithms. As precision medicine advances, the prospect of individualized therapy tailored to each patient’s molecular and clinical profile becomes increasingly attainable.

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8. Verstovsek S, Mesa RA, Rhoades SK, et al. Results of the PERSIST-2 phase 3 study of pacritinib versus best available therapy in myelofibrosis patients with severe thrombocytopenia. J Clin Oncol. 2021;39(8):881-891. doi:10.1200/JCO.20.02465

9. Mesa RA, Kiladjian JJ, Catalano JV, et al. Momelotinib versus ruxolitinib in JAK inhibitor-naïve patients with myelofibrosis (MOMENTUM): Results of a phase 3 trial. Lancet Haematol. 2022;9(5):e365-e376. doi:10.1016/S2352-3026(22)00101-7

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